Abstract Multiple myeloma (MM) is a B cell malignancy characterized by a clonal proliferation of malignant plasma cells in the bone marrow (BM), the presence of high levels of monoclonal serum antibody, and the development of bone lesions. Despite the introduction of a number of novel treatments MM patients still are confronted with an average survival time of 5-7 years. Emerging evidence suggests that the endosteal niche at the bone-BM interface fosters the survival of drug-resistant MM cells, especially through adhesive interactions with osteoblasts, and is therefore responsible for relapse. Currently, treatment options for MM patients are evaluated mainly on the basis of clinical features and historical population response rates. Therefore, an important unmet clinical need is to develop the ability to select the best therapy for an individual based on the ex vivo response of the patient's MM cells (PMMCs) to drug treatment options. This precision medicine approach is expected to provide a transformative means of: (1) reducing ineffective therapies, (2) minimizing excess toxicity and cost, (3) inhibiting the development of the tumor cells' cross-resistance to additional drugs as a critical part of the long-term care of MM patients, and (4) assessing the probability of relapse occurrence. A major challenge, however, is the lack of clinically relevant, high-throughput and inexpensive models that preserve primary patient biospecimen for downstream analyses and use. The goal of this R33 project is to improve and validate a multiple myeloma (MM) culture platform, which was developed through the prior R21 award to enable the ex vivo preservation of PMMCs derived from BM biospecimens. The specific aims of the project are to: (1) increase the culture platform's high- throughput operation capability by implementing a gravity-driven, pumpless flow control strategy while preserving the feasibility of producing the device using industry standard materials and manufacturing practice and (2) prospectively correlate the ex vivo chemosensitivity and resistance of PMMCs with clinical response as a means of validating the predictive capability of our ex vivo MM culture platform and expand drug-resistant PMMCs for downstream characterization as a potential means of guiding subsequent treatment selection. Anticipated results will validate that ex vivo preserved MM biospecimens can be widely used with our culture platform for screening patient-specific treatment options as well as for other applications such as preclinical evaluation of new therapeutics, studying drug-resistant PMMC populations, identifying novel therapeutic targets, and ex vivo models of breast and prostate cancers that metastasize to BM and bone.